Pharmacology (phl 210) Nervous System



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Pharmacology (PHL 210)




Nervous System

Types of Nervous System



Anatomic and neurotransmitter features of peripheral nervous system.





The major components of the central and peripheral nervous systems and their functional relationships



Stimuli from the environment convey information to processing circuits within the brain and spinal cord, which in turn interpret their significance and send signals to peripheral effectors that move the body and adjust the workings of its internal organs.





1. Peripheral Nervous System


Drugs Affecting Motor Function

      • The smallest structural unit of skeletal musculature is the striated muscle fiber. It contracts in response to an impulse of its motor nerve.

      • Neuromuscular transmission of motor nerve impulses to the striated muscle fiber takes place at the motor endplate. The nerve impulse liberates acetylcholine (ACh) from the axon terminal. ACh binds to nicotinic cholinoceptors at the motor endplate. Activation of these receptors causes depolarization of the endplate, from which a propagated action potential is elicited in the surrounding sarcolemma. The action potential triggers a release of Ca2+ from its storage organelles, the sarcoplasmic reticulum (SR), within the muscle fiber; the rise in Ca2+ concentration induces a contraction of the myofilaments (electromechanical coupling).

      • Meanwhile, ACh is hydrolyzed by acetylcholinesterase; excitation of the endplate subsides.

      • If no action potential follows, Ca2+ is taken up by the SR and the myofilaments relax.

      • Clinically important drugs (with the exception of dantrolene) all interfere with neural control of the muscle cell.

      • Centrally acting muscle relaxants, lower muscle tone by augmenting the activity of intraspinal inhibitory interneurons. They are used in the treatment of painful muscle spasms, e.g., in spinal disorders. Benzodiazepines enhance the effectiveness of the inhibitory transmitter GABA at GABAA receptors. Baclofen stimulates GABAB receptors. Executing α2-Adrenoceptor agonists such as clonidine and tizanidine probably act presynaptically to inhibit release of excitatory amino acid transmitters.

      • The convulsant toxins, tetanus toxin (cause of wound tetanus) and strychnine diminish the efficacy of interneuronal synaptic inhibition mediated by the amino acid glycine. As a consequence of an unrestrained spread of nerve impulses in the spinal cord, motor convulsions develop. The involvement of respiratory muscle groups endangers life.

      • Botulinum toxin from Clostridium botulinum is the most potent poison known. The toxin blocks exocytosis of ACh in motor (and also parasympathetic) nerve endings. Death is caused by paralysis of respiratory muscles. Injected intramuscularly at minuscule dosage, botulinum toxin type A is used to treat blepharospasm (twitch of the eyelid), and strabismus (eyes are not properly aligned with each other). A pathological rise in serum Mg2+ levels also causes inhibition of ACh release, hence inhibition of neuromuscular transmission.

      • Dantrolene interferes with electromechanical coupling in the muscle cell by inhibiting Ca2+ release from the SR. It is used to treat painful muscle spasms attending spinal diseases and skeletal muscle disorders involving excessive release of Ca2+ (malignant hyperthermia).

Mechanisms for influencing skeletal muscle tone.



Inhibition of neuromuscular transmission and electromechanical coupling



Muscle Relaxants

  • Muscle relaxants cause a flaccid paralysis of skeletal musculature by binding to motor endplate cholinoceptors, thus blocking neuromuscular transmission.

  • According to whether receptor occupancy leads to a blockade or an excitation of the endplate, one distinguishes non-depolarizing from depolarizing muscle relaxants.

  • As adjuncts to general anesthetics, muscle relaxants help to ensure that surgical procedures are not disturbed by muscle contractions of the patient.




    1. Nondepolarizing muscle relaxants

  • Curare is the term for plant-derived arrow poisons of South American natives.

  • When struck by a curare-tipped arrow, an animal suffers paralysis of skeletal musculature within a short time after the poison spreads through the body; death follows because respiratory muscles fail (respiratory paralysis).

  • Killed game can be eaten without risk because absorption of the poison from the gastrointestinal tract is virtually nil.

  • The curare ingredient of greatest medicinal importance is d-tubocurarine.

  • d-Tubocurarine is given by i.v. injection.

  • It binds to the endplate nicotinic cholinoceptors without exciting them, acting as a competitive antagonist towards ACh. By preventing the binding of released ACh, it blocks neuromuscular transmission.

  • Muscular paralysis develops within about 4 min and lasts about 30 min.

  • d-Tubocurarine does not penetrate into the CNS.

  • The patient would thus experience motor paralysis and inability to breathe, while remaining fully conscious but incapable of expressing anything. For this reason, care must be taken to eliminate consciousness by administration of an appropriate drug (general anesthesia) before using a muscle relaxant.

  • The duration of the effect of d-tubocurarine can be shortened by administering an acetylcholinesterase inhibitor, such as neostigmine. Inhibition of ACh breakdown causes the concentration of ACh released at the endplate to rise. Competitive “displacement” by ACh of d-tubocurarine from the receptor allows transmission to be restored.

  • Unwanted adverse effects produced by d-tubocurarine result from a non-immune mediated release of histamine from mast cells, leading to bronchospasm, urticaria, and hypotension. More commonly, a fall in blood pressure can be attributed to ganglionic blockade by d-tubocurarine.

  • Pancuronium is a synthetic compound now frequently used and not likely to cause histamine release or ganglionic blockade. It is approx. 5-fold more potent than d-tubocurarine, with a somewhat longer duration of action.

  • Increased heart rate and blood pressure are attributed to blockade of cardiac M2-cholinoceptors, an effect not shared by newer pancuronium congeners such as vecuronium and pipecuronium.

  • Other non-depolarizing muscle relaxants include: alcuronium, gallamine, mivacurium, and atracurium. The latter undergoes spontaneous cleavage and does not depend on hepatic or renal elimination.


Non-depolarizing muscle relaxants



2. Depolarizing Muscle Relaxants

  • In this drug class, only succinylcholine (succinyldicholine, suxamethonium) is of clinical importance.

  • Structurally, succinylcholine can be described as a double ACh molecule.

  • Like ACh, succinylcholine acts as agonist at endplate nicotinic cholinoceptors, but it produces muscle relaxation.

  • Unlike ACh, it is not hydrolyzed by acetylcholinesterase. However, it is a substrate of nonspecific plasma cholinesterase (serum cholinesterase).

  • Succinylcholine is degraded more slowly than is ACh and therefore remains in the synaptic cleft for several minutes, causing an endplate depolarization of corresponding duration. This depolarization initially triggers a propagated action potential in the surrounding muscle cell membrane, leading to contraction of the muscle fiber. After its i.v. injection, fine muscle twitches (fasciculations) can be observed.

  • A new action potential can be obtained near the endplate only if the membrane has been allowed to repolarize.

  • The action potential is due to opening of voltage gated Na-channel proteins, allowing Na+ ions to flow through the sarcolemma and to cause depolarization. After a few milliseconds, the Na channels close automatically (“inactivation”), the membrane potential returns to resting levels, and the action potential is terminated. As long as the membrane potential remains incompletely repolarized, renewed opening of Na channels, hence a new action potential, is impossible.

  • In the case of released ACh, rapid breakdown by ACh esterase allows repolarization of the endplate and hence a return of Na channel excitability in the adjacent sarcolemma.

  • With succinylcholine, however, there is a persistent depolarization of the endplate and adjoining membrane regions. Because the Na channels remain inactivated, an action potential cannot be triggered in the adjacent membrane. Because most skeletal muscle fibers are innervated only by a single endplate, activation of such fibers, with lengths up to 30 cm, entails propagation of the action potential through the entire cell. If the action potential fails, the muscle fiber remains in a relaxed state.

  • The effect of a standard dose of succinylcholine lasts only about 10 min. It is often given at the start of anesthesia to facilitate intubation of the patient.

  • As expected, cholinesterase inhibitors are unable to counteract the effect of succinylcholine.

  • In the few patients with a genetic deficiency in pseudocholinesterase (= non-specific cholinesterase), the succinylcholine effect is significantly prolonged causing succinylcholine apnea.

  • Since persistent depolarization of endplates is associated with an efflux of K+ ions, hyperkalemia can result (risk of cardiac arrhythmias).

Action of the depolarizing muscle relaxant succinylcholine



B. Drugs Acting on the Parasympathetic Nervous System

Responses to activation of the parasympathetic system: Parasympathetic nerves regulate processes connected with energy assimilation (food intake, digestion, absorption) and storage. These processes operate when the body is at rest,

  • Allowing a decreased tidal volume (increased bronchomotor tone) and decreased cardiac activity.

  • Secretion of saliva and intestinal fluids promotes the digestion of foodstuffs; transport of intestinal contents is speeded up because of enhanced peristaltic activity and lowered tone of sphincteric muscles.

  • To empty the urinary bladder (micturition), wall tension is increased by detrusor activation with a concurrent relaxation of sphincter tonus.

  • Activation of ocular parasympathetic fibers results in narrowing of the pupil and increased curvature of the lens, enabling near objects to be brought into focus (accommodation).


Acetylcholine (ACh) as a transmitter:

  • ACh serves as mediator at terminals of all postganglionic parasympathetic fibers, in addition to fulfilling its transmitter role at ganglionic synapses within both the sympathetic and parasympathetic divisions and the motor endplates on striated muscle.

  • However, different types of receptors are present at these synaptic junctions, they are Muscarinic (M) and Nicotinic (N) receptors.

  • The existence of distinct cholinoceptors at different cholinergic synapses allows selective pharmacological interventions.


Responses to parasympathetic activation




Acetylcholine: release, effects, and degradation


  • Acetylcholine (ACh) is the transmitter at postganglionic synapses of parasympathetic nerve endings. It is highly concentrated in synaptic storage vesicles densely present in the axoplasm of the terminal. ACh is formed from choline and acetylcoenzyme A, a reaction catalyzed by the enzyme choline acetyltransferase. The highly polar choline is actively transported into the axoplasm. The specific choline transporter is localized exclusively to membranes of cholinergic axons and terminals.

  • During activation of the nerve membrane, Ca2+ is thought to enter the axoplasm and to activate protein kinases. As a result, vesicles discharge their contents into the synaptic gap.

  • ACh quickly diffuses through the synaptic gap. At the postsynaptic effector cell membrane, ACh reacts with its receptors.

  • Released ACh is rapidly hydrolyzed and inactivated by a specific acetylcholinesterase, present on pre- and post-junctional membranes, or by a less specific serum cholinesterase, a soluble enzyme present in serum and interstitial fluid.

  • Muscarinic-cholinoceptors (M) can be classified into M1, M2, and M3 subtypes. M1 receptors are present on nerve cells, e.g., in ganglia, where they mediate a facilitation of impulse transmission from preganglionic axon terminals to ganglion cells. M2 receptors mediate acetylcholine effects on the heart: decrease heart rate. M3 receptors are in smooth muscle, e.g., in the gut and bronchi, where their activation causes increase in muscle tone. M3 receptors are also found in glandular epithelia to increase the secretory activity.

Acetylcholine: release, effects, and degradation


Parasympathomimetics

Acetylcholine (ACh) is too rapidly hydrolyzed and inactivated by acetylcholinesterase (AChE) to be of any therapeutic use; however, its action can be mimicked by other substances, namely direct or indirect parasympathomimetics.



Direct Parasympathomimetics.

  • Carbachol, activates Muscarinic-cholinoceptors, but is not hydrolyzed by AChE. Carbachol can thus be effectively employed for local application to the eye (glaucoma) and systemic administration (bowel atonia, bladder atonia).

  • Pilocarpine and Arecoline also act as direct parasympathomimetics. As tertiary amines, they moreover exert central effects. The central effect of muscarine like substances consists of a refreshing, mild stimulation that is probably the effect desired in betel chewing, a widespread habit in South Asia. Of this group, only pilocarpine enjoys therapeutic use, which is limited to local application to the eye in glaucoma.

Indirect Parasympathomimetics.

AChE can be inhibited selectively, with the result that ACh released by nerve impulses will accumulate at cholinergic synapses and cause prolonged stimulation of cholinoceptors. Inhibitors of AChE are, therefore, indirect parasympathomimetics. Their action is evident at all cholinergic synapses. Chemically, these agents include



  • Esters of carbamic acid (carbamates such as physostigmine and neostigmine)

  • Phosphoric acid (organophosphates such as paraoxon and parathion)

Members of both groups react like ACh with AChE and can be considered false substrates. The esters are hydrolyzed upon formation of a complex with the enzyme. The rate-limiting step in ACh hydrolysis is deacetylation of the enzyme, which takes only milliseconds, thus permitting a high turnover (yield) rate and activity of AChE.

  • De-carbaminoyl-ation following hydrolysis of carbamates takes hours to days, the enzyme remaining inhibited as long as it is carbaminoylated.

  • Cleavage of the phosphate residue, i.e. de-phosphoryl-ation, is practically impossible; enzyme inhibition is irreversible.


Uses of parasympathomimetics

  1. In postoperative atonia of the bowel or bladder (neostigmine).

  2. In myasthenia gravis to overcome the relative ACh-deficiency at the motor endplate

  3. In de-curarization before discontinuation of anesthesia to reverse the neuromuscular blockade caused by non-depolarizing muscle relaxants.

  4. As antidote in poisoning with parasympatholytic drugs because it has access to AChE in the brain (physostigmine).

  5. In the treatment of glaucoma (neostigmine, pyridostigmine, physostigmine pilocarpine paraoxon and ecothiopate): however, their long-term use leads to cataract formation.

  6. Insecticides (parathion). Although they possess high acute toxicity in humans, they are more rapidly degraded than is the insecticide DDT following their emission into the environment.

  7. Tacrine is not an ester and interferes only with the choline-binding site of AChE. It is effective in alleviating symptoms of dementia in some subtypes of Alzheimer’s disease.

Direct and indirect parasympathomimetics



Parasympatholytics

Excitation of the parasympathetic division of the autonomic nervous system causes release of acetylcholine at neuroeffector junctions in different target organs. The major effects are summarized in the following Figure (blue arrows). Some of these effects have therapeutic applications, as indicated by the clinical uses of parasympathomimetics. Substances acting antagonistically at the M-cholinoceptor are designated parasympatholytics (prototype: the alkaloid atropine; actions shown in red in the panels). Therapeutic use of these agents is complicated by their low organ selectivity.



Possibilities for a targeted action include:

  • Local application.

  • Selection of drugs with either good or poor membrane penetrability as the situation demands.

  • Administration of drugs possessing receptor subtype selectivity.


Uses of Parasympatholytics:

Parasympatholytics are employed for the following purposes:

  • Inhibition of exocrine glands as Bronchial secretion.

    1. Premedication with atropine before inhalation anesthesia prevents a possible hypersecretion of bronchial mucus, which cannot be expectorated by coughing during intubation (anesthesia).

    2. Gastric secretion. Stimulation of gastric acid production by vagal impulses involves an M-cholinoceptor subtype (M1-receptor), probably associated with enterochromaffin cells. Pirenzepine displays a preferential affinity for this receptor subtype. Pirenzepine was formerly used in the treatment of gastric and duodenal ulcers.

  • Relaxation of smooth musculature.

  1. Bronchodilation can be achieved by the use of ipratropium in conditions of increased airway resistance (chronic obstructive bronchitis, bronchial asthma). When administered by inhalation, this quaternary compound has little effect on other organs because of its low rate of systemic absorption.

  2. Spasmolysis by N-butylscopolamine in biliary or renal colic. Because of its quaternary nitrogen, this drug does not enter the brain and requires parenteral administration. Its spasmolytic action is especially marked because of additional ganglionic blocking and direct muscle-relaxant actions.

  3. Lowering of pupillary sphincter tonus and pupillary dilation by local administration of homatropine or tropicamide (mydriatics) allows observation of the ocular fundus. For diagnostic uses, only short-term pupillary dilation is needed. The effect of both agents subsides quickly in comparison with that of atropine (duration of several days).

  • Cardio-acceleration.

  1. Ipratropium is used in bradycardia and AV-block, respectively, to raise heart rate and to facilitate cardiac impulse conduction. As a quaternary substance, it does not penetrate into the brain, which greatly reduces the risk of CNS disturbances. Relatively high oral doses are required because of an inefficient intestinal absorption.

  2. Atropine may be given to prevent cardiac arrest resulting from vagal reflex activation, incident to anesthetic induction, gastric lavage, or endoscopic procedures.

  • CNS-dampening effects.

  1. Scopolamine is effective in the prophylaxis of kinetosis (motion sickness, sea sickness); it is well absorbed transcutaneously. Scopolamine penetrates the blood-brain barrier faster than does atropine. In psychotic excitement (agitation), sedation can be achieved with scopolamine. Unlike atropine, scopolamine exerts a calming and amnesiogenic action that can be used to advantage in anesthetic premedication.

  2. Symptomatic treatment in parkinsonism for the purpose of restoring a dopaminergic-cholinergic balance in the corpus striatum. Antiparkinsonian agents, such as benzatropine, readily penetrate the blood-brain barrier. At centrally equi-effective dosage, their peripheral effects are less marked than are those of atropine.

Contraindications for parasympatholytics

  • Glaucoma: Since drainage of aqueous humor is impeded during relaxation of the pupillary sphincter, intraocular pressure rises.

  • Prostatic hypertrophy with impaired micturition: loss of parasympathetic control of the detrusor muscle exacerbates difficulties in voiding urine.


Atropine poisoning

  • Peripheral: tachycardia; dry mouth; hyperthermia secondary to the inhibition of sweating. Although sweat glands are innervated by sympathetic fibers, these are cholinergic in nature. When sweat secretion is inhibited, the body loses the ability to dissipate metabolic heat by evaporation of sweat. There is a compensatory vasodilation in the skin allowing increased heat exchange through increased cutaneous blood flow. Decreased peristaltic activity of the intestines leads to constipation.

  • Central: Motor restlessness, progressing to maniacal agitation, psychic disturbances, disorientation, and hallucinations. Elderly subjects are more sensitive to such central effects. In this context, the diversity of drugs producing atropine-like side effects should be borne in mind: e.g., tricyclic antidepressants, neuroleptics, antihistamines, antiarrhythmics, antiparkinsonian agents.

  • Apart from symptomatic, general measures (gastric lavage, cooling with ice water), therapy of severe atropine intoxication includes the administration of the indirect parasympathomimetic physostigmine. The most common instances of “atropine” intoxication are observed after ingestion of the berry-like fruits of belladonna (children) or intentional overdosage with tricyclic antidepressants in attempted suicide.


Effects of parasympathetic stimulation and blockade



Parasympatholytics





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